Recrystallization-free estradiol-containing patch

ABSTRACT

An active substance-containing patch for the controlled release of estradiol or its pharmaceutically acceptable derivatives alone or combined with gestagens, comprising a backing layer, an active substance-containing reservoir which is bonded thereto and produced by using pressure-sensitive adhesives, and a removable protective layer, is characterized by the fact that the pressure-sensitive adhesive comprises ethylcellulose, esters of non-hydrogenated and/or hydrogenated colophony, and lauric acid.

This application is a 371 of PCT/EP95/05005, filed Dec. 18, 1995.

BACKGROUND OF THE INVENTION

The present invention relates to an active substance-containing patchfor the controlled release of estradiol or its pharmaceuticallyacceptable derivatives either alone or combined with gestagens, to humanor animal skin, comprising a pressure-sensitive adhesive ofethylcellulose, esters of colophony, and lauric acid. The presentinvention further relates to its use and to a process for itsproduction.

Estrogen-containing patches have been known for some time. However,these patches are disadvantageous in that they either contain ethanol orinvolve the potential danger of active substance recrystallization inthe course of time.

It is known from DE-OS 32 05 258 and EP 0 285 563 to administerestradiol and ethanol simultaneously in a patch formulation. However,the production of this patch is very expensive, and there is a lowwearing comfort after application because of inflexibility.

EP 0 285 563 describes a transdermal therapeutic system for the combinedapplication of estrogens and gestagens. The reservoir comprises theactive substance formulation, and optionally a membrane, as well asethanol as a percutaneous absorption improving agent. Since the activesubstance release is primarily controlled by the membrane, thistransdermal therapeutic system is completely different from the activesubstance-containing patch according to the present invention. In thepatch described in said publication, the adhesive has the mere functionof fastening the patch to the skin. The fact that it can contribute tothe control of the active substance release is not its main function butmerely a--probably even undesired--side effect. It is a so-called "pouchpatch" since the active substance preparation is present in a pouchconsisting of an impermeable backing layer and a membrane having anadhesive layer. Owing to its complicated structure production of thispatch is very expensive since the individual components have to bemanufactured separately and then joined in an additional step to form apatch.

Unlike the single-layer system according to the present invention EP 0275 716 describes a two-layer transdermal system for the simultaneousadministration of one or several estrogens which are dissolved ormicrodispersed in the polymeric layer. In addition to the activesubstances, the pressure-sensitive adhesive layer comprises substancesimproving the transdermal absorption. Polymeric and pressure-sensitiveadhesive layer may consist of polyacrylates, silicones, orpolyisobutylenes.

EP 0 072 251 describes a flexible, liquid-absorbing medicinal bandage.The substrate attached to the flexible backing layer consists of ahydrophilic matrix based on hydrophilic high-molecular polysaccharidesand/or polyacrylic acid, polyacrylamide, ethylene-vinylacetate-copolymers, and other polymers, as well as of a liquid phasebased on a solution or emulsion of carbohydrate, proteins, polyhydricalcohols, and different active substances, amongst others hormones. Themain feature of this invention is the moisture-absorbing adhesive.

EP 0 328 806 describes a transdermal therapeutic system withoutmembrane; its matrix consists of a polyacrylate adhesive, a solvent, apenetration enhancer, and estrogen, its derivatives and combinationsthereof.

WO 87/07 138 describes an estradiol patch having a backing layer, anactive substance-containing matrix, and a pressure-sensitive adhesivecovered with a removable protective layer. Matrix and pressure-sensitiveadhesive are manufactured in operations involving considerabletechnological expenditure, i.e., by homogenizing, degassing, coating,drying, and separating. According to an embodiment the backing layer hasto be coated with a pressure-sensitive adhesive, requiring an additionaloperation. The individual parts are joined in a separate step. For thisreason, the production of this patch is very expensive and complicated.

U.S. Pat. No. 4,624,665 describes systems comprising the activesubstance in microencapsulated form within the reservoir. The reservoiris embedded between backing layer and a membrane. The outer edge of thesystem is provided with a pressure-sensitive adhesive. Structure andproduction of this system are very complicated since the activesubstance has to be microencapsulated and homogeneously dispersed in aliquid phase which is then embedded between backing layer and membranein further operations. Moreover, this system must then be provided withan adhesive edge and covered with a protective layer.

EP 0 186 019 describes active substance patches wherein water-swellablepolymers are added to a rubber/adhesive-resin-mass and from whichestradiol can be released. It turned out, however, that the estradiolrelease from these active substance patches is absolutely insufficientand fails to meet the therapeutic requirements.

DE-OS 20 06 969 describes a patch or a pressure-sensitive adhesivedressing exhibiting system action, wherein contraceptive substances areincorporated in the adhesive component or in the adhesive film. Theadhesive film may be an acrylate.

DE-OS 39 33 460 describes an estrogen-containing active substance patchbased on homo and/or copolymers with at least one derivative of acrylicacid or with methacrylic acid combined with water-swellable substances.

However, it turned out that the active substance release ofpressure-sensitive adhesive transdermal therapeutic matrix systems whichcomprise the active substance in a partially or completely dissolvedform is absolutely insufficient; moreover, they involve the potentialrisk that the active substance recrystallizes in the course of time. Asa result the active substance release decreases, and theestrogen-containing patch does no longer meet the therapeuticrequirements.

SUMMARY OF THE INVENTION

Accordingly, it is the object of the present invention to avoid theaforementioned drawbacks and to provide a stable, i.e.,recrystallization-free, estrogen-containing patch having a sufficientactive substance release which does not change through storage.

Most surprisingly, it turned out that this object is achieved by anestrogen-containing pressure-sensitive adhesive of ethylcellulose,esters of colophony, and lauric acid.

Accordingly, the above object is achieved by an activesubstance-containing patch according to the main claim. The subclaimsrelate to particularly preferred embodiments of the subject matteraccording to the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Thus the present invention relates to an active substance-containingpatch for the controlled release of estradiol or its pharmaceuticallyacceptable derivatives alone or combined with gestagens, consisting of abacking layer, an active substance-containing reservoir which is bondedthereto and is produced by using pressure-sensitive adhesives, and aremovable protective layer, the pressure-sensitive adhesive comprisingethylcellulose, esters of non-hydrogenated and/or hydrogenatedcolophony, and lauric acid.

Ethylcellulose is a cellulose ether produced by reacting ethyl chloridewith alkali cellulose. With respect to the structure, it is generallyassumed that a cellulose molecule is a chain of anhydroglucose orcellobiose units bound by oxygen bridges. These long chains ofanhydroglucose with oxygen bridges are very stable and have goodflexibility. These properties are utilized in the estradiol-containingpatch according to the present invention to render thepressure-sensitive adhesive sufficiently cohesive, this is required toremove the patch from the skin without leaving any residue aftercompleted application. The pressure-sensitive adhesive comprisesethylcellulose in a proportion of 5-25% wt., preferably 8-14% wt.

Examples of esters of colophony include, for example, methyl ester,glycerol ester, pentaerythritol ester, pentaerythritol ester modifiedwith maleic acid, glycerol ester modified with maleic acid, andtriethylene glycol ester. The proportion of colophony esters in theestradiol-containing pressure-sensitive adhesive amounts to 50-90% wt.,preferably 60-80% wt.

The pressure-sensitive adhesive may comprise esters of hydrogenatedcolophony either alone or together with esters of non-hydrogenatedcolophony.

Particularly preferred esters of colophony include triethylene glycolester, glycerol ester, and pentaerythritol ester of hydrogenatedcolophony.

Lauric acid is a basic carboxylic acid having 12 C-atoms. It increasesthe penetration of estradiol through the skin. The mechanism is stillopen. The proportion of lauric acid contained in the pressure-sensitiveadhesive amounts to 1-20% wt., preferably 2-15 % wt.

The reservoir of the recrystallization-free, estradiol-containing patchwith sufficient active substance release comprises estradiol and itspharmaceutically acceptable derivatives alone or in combination withgestagens at a total concentration of 1∝15% wt., relative to all of thereservoir components, namely in a molar ratio of 1:1 to 1:10.

The estradiol-containing reservoir may comprise at least one componentof the group including anti-ageing agents, plasticizers, antioxidants,and absorption improvers. Suitable plasticizers are known to thoseskilled in the art and are described, for example, in DE 37 43 946.Usually, the proportion of plasticizers in the estradiol-containingreservoir amounts to up to 5%-wt.

In addition, the active substance-containing reservoir also comprisesanti-ageing agents in a concentration of up to 1% wt. These are known tothe skilled artisan and are described, for example, in DE 37 43 946.

The materials for the impermeable backing layer and the removableprotective layer are also known to the skilled artisan (e.g., DE 38 43239).

The estradiol-containing reservoir may either be produced from solutionor from the melt.

Moreover, the reservoir may consist of several layers.

In case the reservoir has an insufficient self-tackiness to the skin, itmay be provided with an additional pressure-sensitive adhesive layerwhich is free from active substances, or with a circumferentialpressure-sensitive adhesive edge. This ensures that the transdermalpatch adheres to the skin over the whole application period.

A particularly preferred structure of the transdermalestradiol-containing patch is a matrix system wherein, as is generallyknown, the matrix controls the active substance release and complieswith the √t-law according to Higuchi. However, it is understood that amembrane system may well be of advantage in particular cases. In thiscase, a membrane controlling the active substance release is locatedbetween the reservoir and the pressure-sensitive adhesive layer.

The thickness of the transdermal patch depends on the therapeuticrequirements and may be adapted accordingly. Usually, it ranges from0.03-0.6 mm.

EXAMPLE 1

75.0 g triethylene glycol ester of hydrogenated colophony (StaybeliteEster 3E/by Hercules) and

10.0 g glycerol ester of hydrogenated colophony (Staybelite Ester 10E/byHercules)

are mixed by kneading at 100° C. for 5 minutes. Then 2.5 g estradiol and2.5 g lauric acid are added. Kneading is continued for 30 minutes. Afterheating to 140° C., 10.0 g ethylcellulose N50NF (by Hercules) are addedin portions, and then kneading is continued for another 2.5 hours.

In a hotmelt coating line (die coating system) the activesubstance-containing adhesive mass thus obtained is coated onto aremovable protective layer (Hostaphan RN 100, coated on one side withsilicone--by Kalle) in such a manner that an active substance-containingreservoir having a mass per unit area of 80 g/m² results. Theimpermeable backing layer (polyester sheet, thickness 15 μm) islaminated on this reservoir. Subsequently, active substance patches of16 cm² are punched.

EXAMPLES 2 AND 3

Manufacture is carried out as described in Example 1, however with theraw materials and quantities as listed in Table 1 (manufacturingformula).

Analytic procedure

The active substance release of the transdermal patches having a size of16 cm² is determined according to the Rotating bottle-method describedin USP XXII in 0.9% salt solution at 37° C.

To measure the guinea pig penetration, the skin of guinea pigs isclamped in the Franz-cell. An estradiol-containing patch having an areaof 2.54 cm² is stuck onto the skin, and the active substance release ismeasured at 37° C. (acceptor medium: 0.9% salt solution). (Literature:Umesh V. Banakar Pharmaceutical dissolution testing (1stedition--1991)).

Testing as to recrystallization is carried out visually against thelight.

The results are listed in Table 2.

                  TABLE 1    ______________________________________    Composition (indications in g)    Ethylcellulose                  Staybelite Ester    Example           N50NF      3E      10E   Lauric acid                                            Estradiol    ______________________________________    1      10.0       75.0    10.0  2.5     2.5    2      10.0       70.0    10.0  7.5     2.5    3      13.0       65.5    9.0   10.0    2.5    ______________________________________

                  TABLE 2    ______________________________________    Results of Analysis           Estradiol           Guinea pig           content  In-vitro release                               skin penetration                                         Recrystal-    Example           μg/16 cm.sup.2                    μg/16 cm.sup.2 · 4 h                               μg/16 cm.sup.2 · 24                                         lization    ______________________________________    1      3200     645        179       no    2      3200     843        157       no    3      3200     1368       180       no    acc. to           3200     1125       95        considerable    DE    3933460    ______________________________________

The Table shows that a clearly improved penetration through the guineapig skin is obtained, as evidenced by the Comparative Example accordingto DE 3933460. Analogously, there is no recrystallization at all in theExamples according to the present invention.

We claim:
 1. A recrystallization-free estradiol-containing patch for thecontrolled release of estradiol or its pharmaceutically acceptablederivatives alone or in combination with at least one gestagen,comprising a backing layer, an active substance-containing reservoir,and a removable protective layer wherein said reservoir is bonded tosaid backing layer and contains a pressure-sensitive adhesive comprising5-25%-wt. ethylcellulose, 50-90%-wt. of esters of non-hydrogenatedand/or hydrogenated colophony, and 1-20%-wt. lauric acid.
 2. The activesubstance-containing patch according to claim 1 wherein thepressure-sensitive adhesive comprises lauric acid in a proportion of2-15%-wt.
 3. The active substance-containing patch according to claim 1wherein the pressure-sensitive adhesive comprises 8-14%-wt. ofethylcellulose.
 4. The active substance-containing patch according toclaim 1 wherein the pressure-sensitive adhesive comprises esters ofcolophony in a proportion of 60-80%-wt.
 5. The activesubstance-containing patch according to claim 1 wherein thepressure-sensitive adhesive comprises estradiol or its pharmaceuticallyacceptable derivatives alone or in combination with at least onegestagen in a proportion of 1-15%-wt.
 6. The active substance-containingpatch according to claim 4 wherein the pressure-sensitive adhesivecomprises estradiol or its pharmaceutically acceptable derivatives aloneor in combination with at least one gestagen at a proportion of1.5-5.0%-wt.
 7. The active substance-containing patch according to claim1 wherein the pressure sensitive adhesive comprises 2-15%-wt. lauricacid, 8-14%-wt. ethylcellulose and 60-80%-wt. colophony.
 8. The activesubstance-containing patch according to claim 1 wherein the backinglayer is impermeable to the components of the reservoir.
 9. The activesubstance-containing patch according to claim 1 wherein the esters ofcolophony are selected from the group consisting of methyl ester,glycerol ester, pentaerythritol ester, pentaerythritol ester modifiedwith maleic acid, glycerol ester modified with maleic acid, andtriethylene glycol ester.
 10. The active substance-containing patchaccording to claim 1 wherein the reservoir comprises estradiol or itspharmaceutically acceptable derivatives in combination with at least onegestagen in a molar ratio of 1:1 to 1:10.
 11. The activesubstance-containing patch according to claim 1 wherein the reservoircomprises at least one component of the group consisting of anti-agingagents, plasticizers, antioxidants, and absorption improvers.
 12. Theactive substance-containing patch according to claim 1 wherein thepressure-sensitive adhesive is a solvent-based pressure-sensitiveadhesive or a hot-melt pressure-sensitive adhesive.
 13. The activesubstance-containing patch according to claim 1 wherein the reservoirconsists of several layers and has an additional pressure-sensitiveadhesive layer which is free from active substances.
 14. The activesubstance-containing patch according to claim 13 wherein a membranewhich controls the active substance release and is located between thereservoir and the pressure-sensitive adhesive layer.
 15. The activesubstance-containing patch according to claim 1 wherein the reservoir isprovided with a circumferential pressure-sensitive adhesive edge. 16.The active substance-containing patch according to claim 1 wherein thethickness of the active substance-containing patch is in the range of0.03-0.6 mm.
 17. A recrystallization-free estradiol-containing patch forthe controlled release of estradiol or its pharmaceutically acceptablederivatives alone or in combination with at least one gestagen,comprising a backing layer, an active substance-containing reservoir,and a removable protective layer, wherein said reservoir is bonded tosaid backing layer and contains a pressure-sensitive adhesive consistingessentially of 5-75% wt. ethylcellulose, 50-90% wt. esters ofnon-hydrogenated and/or hydrogenated colophony and 1-20% wt. lauricacid.
 18. A method of using the active substance-containing patchaccording to claim 1 or 17 for therapeutic purposes in human andveterinary medicine or in cosmetics comprising removing the saidremovable protective layer from the patch and placing the patch on theskin of a human or animal.